Job Syndrome
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Autosomal dominant hyperimmunoglobulin E (IgE) syndrome (HIES) was first described as Job syndrome in 1966 [1] and included the triad of eosinophilia, eczema, and recurrent skin and pulmonary infections (named after the biblical character Job, who was “smote with sore boils”). Elevated IgE level was recognized as a cardinal feature of the syndrome in 1972, and the name HIES was subsequently proposed. [2] The phenotype was later expanded to include many connective tissue and skeletal abnormalities. A scoring system that weighted both the immunologic and somatic features of the syndrome was designed to aid in the clinical diagnosis of these patients (see the table below). [3]
Table. Scoring System for Job Syndrome (Open Table in a new window)
0
1
2
3
4
5
6
7
8
10
Clinical Findings
Highest IgE (IU/mL)
< 200
200-500
501-1000
1001-2000
>2000
Total # skin abscesses/boils
None
1-2
3-4
>4
Total # pneumonias
None
1
2
3
>3
Parenchymal lung abnormalities
None
Bronchiectasis
Pneumatocele
Other serious infection
None
Present
Fatal infection
None
Present
Highest eosinophils/uL
< 700
701-800
>800
Newborn rash
None
Present
Eczema (worst stage)
None
Mild
Moderate
Severe
Sinusitis/otitis (# in worst year)
1-2
3
4-6
>6
Candidiasis
None
Oral, vaginal
Fingernail
Systemic
Retained primary teeth
None
1
2
3
>3
Scoliosis (max. curvature)
< 10
10-14
15-20
>20
Minimal trauma fractures
None
1-2
>2
Hyperextensibility
None
Present
Characteristic face
None
Mild
Present
Increased interalar distance
< 1 SD
1-2 SD
>2 SD
High palate
None
Present
Congenital anomaly
None
Present
Lymphoma
None
Present
More recently, vascular abnormalities, including coronary aneurysm without atherosclerosis, and brain MRI abnormalities, including focal hyperintensities and Chiari I malformations, have been described. In 2007, autosomal dominant mutations in signal transducer and activator of transcription-3 (STAT3) gene were identified as the molecular cause of this disease. [4, 5, 6] See image below.
Mutations in the STAT3 gene have been identified in almost all cases of clinically verified HIES. [7, 8] STAT3 is one of 7 human STAT (signal transducer and activator of transcription) proteins, which are critical second messengers for many cytokine, hormone, and growth factor receptors. In general, Janus family tyrosine kinases (JAKs) bind to the intracellular components of cytokine receptors, and are, in turn, bound by STATs upon cytokine signaling. When cytokines bind to their cognate receptor, JAKs phosphorylate the cytokine receptor and subsequently the STATs, which then dissociate from the JAK-receptor complex. Phosphorylated STATs dimerize within the cytosol via their phosphotyrosines and Src-homology 2 (SH2) domains. Dimerized STATs then translocate to the nucleus, where they bind DNA in the promoter sequences of target genes to activate transcription. This activity is typically stopped by STAT dephosphorylation. STAT3 is located on human chromosome17q21.
STAT3 mutations have been found in persons of Asian, African, Caucasian, and Hispanic descent and correlate well with HIES disease. The mutations are predominantly missense and in-frame deletions that lead to production of proteins with dominant negative activity. No null alleles have been identified to date, indicating that haploinsufficiency is not a mechanism for disease causation. Most HIES STAT3 mutations are located in the SH2 and DNA binding regions. Dominant negative mutants antagonize the wild type protein, leading to less than 50% STAT3 activity. This is consistent with the mouse data, which show that heterozygous STAT3 deficiency is not associated with disease, while STAT3 null animals die during embryogenesis. Therefore, HIES patients have less than 50% STAT3 activity, which is enough to sustain life and many aspects of development but inadequate for normal immune function or normal continued tissue remodeling.
HIES is a disease of both too little and too much inflammatory response, which is in part explained by the important role of STAT3 in the induction and signalling of key cytokines, including interleukins IL-6, IL-10, IL-17, IL-22, and IL-23. IL-6 induces acute phase proteins by hepatocytes, neutrophil production in cooperation with colony-stimulating growth factors, stimulation of differentiated B cell growth, stimulation of proinflammatory cytokine production (particularly IL-17), inhibition of the action and production of regulatory T cells, and upregulation of the chemokine MCP-1 (also known as CCL2).
Due to impaired IL-6 and IL-23 signalling through STAT3, the crucial T cell transcription factor retinoid-related orphan receptor gamma (ROR-gt) is diminished, impairing IL-17 expression and Th17 differentiation. [9] Th17 cells are T helper cells that produce IL-17, a cytokine important in neutrophil recruitment and activation and defense against fungal and extracellular bacteria. Th17 cells also produce IL-22, which stimulates epithelial production of b-defensins, small peptides crucial for killing bacteria and fungi. These cytokines, which are inadequately upregulated in HIES, may explain some of the susceptibility to infections of the skin and lung epithelium.
Overexuberant inflammation in HIES is suggested by the frequent development of pneumatoceles following pneumonias, despite adequate therapy of pathogens. Transcriptional array studies and cytokine production studies both show increased proinflammatory cytokines such as tumor necrosis factor alpha (TNFa), interferon gamma (IFNg), and IL-12 in HIES cells compared to normals. Abnormally low IL-10, a cytokine critical for dampening the inflammatory response, may also contribute to the exuberant inflammatory response in HIES. IL-10 signaling is mediated via STAT3. IL-10 has negative feedback regulation of macrophages, which express costimulators that enhance T cell activation and secrete cytokines such as IL-12 and IL-23 to enhance cell-mediated immunity. Therefore, impaired IL-10 production and signaling may be associated with increased proinflammatory cytokines. It may even contribute to the increased IgE and eosinophilia in HIES due to the lack of normal IL-4 suppression.
United States
HIES is a rare disease, although the exact incidence is unknown. It has no known associations with race, ethnicity, or gender.
HIES is associated with a contracted lifespan, with deaths occurring predominantly in adulthood due to the consequences of chronic infections. In a recent review of a large cohort of patients, the average living patient age was 27 years, but ages ranged from 3-58 years. Infection-related deaths occurred at an average age of 29 years.
Death in HIES patients are most commonly due to chronic pulmonary infections in the setting of pneumatoceles or bronchiectasis or both. Molds, such as Aspergillus and Scedosporium species, may invade the pulmonary blood vessels, leading to metastatic spread or fatal hemoptysis. These infections are secondary opportunists in regions of destroyed lung caused by the inappropriate healing of previous infections. [10]
HIES patients are at increased risk for Hodgkin and non-Hodgkin lymphoma (relative risk 259), although the number of cases reported is small. [11]
STAT3 mutations have been detected in persons of Caucasian, African, Asian, and Hispanic descent. Although most documented cases are in white patients, this is likely due to referral bias of the population studied.
No gender-based differences have been described with regard to disease severity or incidence.
In a recent chart review, the average age of diagnosis was 11.5 years. However, the diagnosis can be made in infancy or adulthood. Proband survival has improved over the years along with improved management, allowing patients to have their own children. Given the autosomal dominant nature of HIES, these offspring of known patients receive early diagnosis and therapy.
Davis SD, Schaller J, Wedgwood RJ. Job’s Syndrome. Recurrent, “cold”, staphylococcal abscesses. Lancet. 1966 May 7. 1(7445):1013-5. [Medline].
Buckley RH, Wray BB, Belmaker EZ. Extreme hyperimmunoglobulinemia E and undue susceptibility to infection. Pediatrics. 1972 Jan. 49(1):59-70. [Medline].
Grimbacher B, Holland SM, Puck JM. Hyper-IgE syndromes. Immunol Rev. 2005 Feb. 203:244-50. [Medline].
Minegishi Y, Saito M, Tsuchiya S, Tsuge I, Takada H, Hara T. Dominant-negative mutations in the DNA-binding domain of STAT3 cause hyper-IgE syndrome. Nature. 2007 Aug 30. 448(7157):1058-62. [Medline].
Holland SM, DeLeo FR, Elloumi HZ, Hsu AP, Uzel G, Brodsky N. STAT3 mutations in the hyper-IgE syndrome. N Engl J Med. 2007 Oct 18. 357(16):1608-19. [Medline].
Sowerwine KJ, Holland SM, Freeman AF. Hyper-IgE syndrome update. Ann N Y Acad Sci. 2012 Feb. 1250:25-32. [Medline].
Chandesris MO, Melki I, Natividad A, Puel A, Fieschi C, Yun L, et al. Autosomal dominant STAT3 deficiency and hyper-IgE syndrome: molecular, cellular, and clinical features from a French national survey. Medicine (Baltimore). 2012 Jul. 91(4):e1-19. [Medline].
Minegishi Y, Saito M. Molecular mechanisms of the immunological abnormalities in hyper-IgE syndrome. Ann N Y Acad Sci. 2011 Dec. 1246:34-40. [Medline].
Milner JD, Brenchley JM, Laurence A, Freeman AF, Hill BJ, Elias KM, et al. Impaired T(H)17 cell differentiation in subjects with autosomal dominant hyper-IgE syndrome. Nature. 2008 Apr 10. 452(7188):773-6. [Medline]. [Full Text].
Freeman AF, Kleiner DE, Nadiminti H, Davis J, Quezado M, Anderson V. Causes of death in hyper-IgE syndrome. J Allergy Clin Immunol. 2007 May. 119(5):1234-40. [Medline].
Leonard GD, Posadas E, Herrmann PC, Anderson VL, Jaffe ES, Holland SM. Non-Hodgkin’s lymphoma in Job’s syndrome: a case report and literature review. Leuk Lymphoma. 2004 Dec. 45(12):2521-5. [Medline].
O’Connell AC, Puck JM, Grimbacher B, Facchetti F, Majorana A, Gallin JI, et al. Delayed eruption of permanent teeth in hyperimmunoglobulinemia E recurrent infection syndrome. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2000 Feb. 89(2):177-85. [Medline].
Ling JC, Freeman AF, Gharib AM, Arai AE, Lederman RJ, Rosing DR. Coronary artery aneurysms in patients with hyper IgE recurrent infection syndrome. Clin Immunol. 2007 Mar. 122(3):255-8. [Medline].
Freeman AF, Collura-Burke CJ, Patronas NJ, et al. Brain abnormalities in patients with hyperimmunoglobulin E syndrome. Pediatrics. 2007 May. 119(5):e1121-5. [Medline].
Ozcan E, Notarangelo LD, Geha RS. Primary immune deficiencies with aberrant IgE production. J Allergy Clin Immunol. 2008 Dec. 122(6):1054-62; quiz 1063-4. [Medline].
Jonczyk-Potoczna K, Szczawinska-Poplonyk A, Warzywoda M, Breborowicz A, Pawlak B. Hyper Ig E syndrome (Job syndrome, HIES) – radiological images of pulmonary complications on the basis of three cases. Pol J Radiol. 2012 Apr. 77(2):69-72. [Medline]. [Full Text].
0
1
2
3
4
5
6
7
8
10
Clinical Findings
Highest IgE (IU/mL)
< 200
200-500
501-1000
1001-2000
>2000
Total # skin abscesses/boils
None
1-2
3-4
>4
Total # pneumonias
None
1
2
3
>3
Parenchymal lung abnormalities
None
Bronchiectasis
Pneumatocele
Other serious infection
None
Present
Fatal infection
None
Present
Highest eosinophils/uL
< 700
701-800
>800
Newborn rash
None
Present
Eczema (worst stage)
None
Mild
Moderate
Severe
Sinusitis/otitis (# in worst year)
1-2
3
4-6
>6
Candidiasis
None
Oral, vaginal
Fingernail
Systemic
Retained primary teeth
None
1
2
3
>3
Scoliosis (max. curvature)
< 10
10-14
15-20
>20
Minimal trauma fractures
None
1-2
>2
Hyperextensibility
None
Present
Characteristic face
None
Mild
Present
Increased interalar distance
< 1 SD
1-2 SD
>2 SD
High palate
None
Present
Congenital anomaly
None
Present
Lymphoma
None
Present
Jennifer Heimall, MD Clinical Fellow, Department of Allergy and Immunology, National Institutes of Health-NIAID
Jennifer Heimall, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American Academy of Pediatrics, American College of Allergy, Asthma and Immunology, American College of Physicians-American Society of Internal Medicine, American Medical Association
Disclosure: Nothing to disclose.
Alexandra Freeman, MD Staff Clinician, Laboratory of Clinical Infectious Diseases, NIAID, NIH
Alexandra Freeman, MD is a member of the following medical societies: American Academy of Pediatrics, Infectious Diseases Society of America, Pediatric Infectious Diseases Society
Disclosure: Nothing to disclose.
Steven M Holland, MD Assistant Professor of Medicine, Department of Medicine, Johns Hopkins Hospital; Chief, Laboratory of Clinical Infectious Diseases, Chief, Infectious Diseases Program, National Institute of Allergy and Infectious Diseases, National Institutes of Health
Steven M Holland, MD is a member of the following medical societies: American Association for the Advancement of Science, American College of Physicians, American Medical Association, American Society for Microbiology, Infectious Diseases Society of America
Disclosure: Nothing to disclose.
Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Received salary from Medscape for employment. for: Medscape.
Michael A Kaliner, MD Clinical Professor of Medicine, George Washington University School of Medicine; Medical Director, Institute for Asthma and Allergy
Michael A Kaliner, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American Association of Immunologists, American College of Allergy, Asthma and Immunology, American Society for Clinical Investigation, American Thoracic Society, Association of American Physicians
Disclosure: Nothing to disclose.
Charles H Kirkpatrick, MD
Charles H Kirkpatrick, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American Association of Immunologists, American College of Physicians, American Society for Clinical Investigation, Clinical Immunology Society, American Federation for Clinical Research
Disclosure: Received consulting fee from Dyax for consulting.
The authors would like to acknowledge the patients with HIES and their families who have generously aided in our understanding of this fascinating syndrome.
Job Syndrome
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